Letter: The Unresolved Issue of <scp>NSBB</scp> Confounding in Statin Research for Cirrhosis—Authors' Reply

We thank Huang and colleagues [1] for their thoughtful letter and for highlighting the critical role of non-selective beta-blockers (NSBBs) as a potential effect modifier in the relationship between statin therapy and clinical outcomes in cirrhosis. We agree that the interplay between statins and NSBBs is central to the pharmacotherapy of portal hypertension, and that heterogeneity in NSBB exposure across studies may introduce confounding and contribute to between-study variability. While our original publication [2] partially addressed this issue via a sensitivity analysis for the haemodynamic outcome of hepatic venous pressure gradient (HVPG), we acknowledge that applying similarly rigorous approaches to clinical endpoints would be informative and could further clarify whether the observed benefits of statins are independent of, or synergistic with, concomitant NSBB therapy. In response to their suggestion, we performed a post hoc sensitivity analysis of all-cause mortality and hepatic decompensation, restricting inclusion to the randomised controlled trials (RCTs) where NSBBs were administered as a standardised co-intervention in both study arms [3-6]. Within this NSBB-standardised subset, statin therapy remained significantly associated with lower all-cause mortality (OR 0.39; 95% CI 0.21–0.74; I2 = 0.0%) (Figure 1A). This finding suggests that the survival benefit of statins may be additive to that of NSBBs and could plausibly reflect pleiotropic effects beyond portal pressure reduction, including improvements in liver microvascular function, nitric oxide regeneration and modulation of systemic inflammation. For hepatic decompensation, the NSBB-standardised subset yielded an OR of 0.68 (95% CI 0.46–1.02; I2 = 0.0%) (Figure 1B). Consistent with the overall RCT analysis, this estimate did not reach conventional statistical significance, although the direction of effect remained protective and aligned with the signal observed across observational studies. This is relevant, as the cardiovascular/metabolic benefits of statins typically emerge with prolonged treatment and are well established in long-term follow-up studies [7, 8]. Accordingly, the absence of statistical significance for decompensation in RCTs may reflect limited follow-up and/or power rather than the absence of a biologically meaningful effect, especially in the light of the consistent mortality and haemodynamic signals. We acknowledge, however, that NSBB use is incompletely and inconsistently reported in observational cohorts, which limits the ability to adequately account for this key covariate. Although adjusted analyses were used where available, observational evidence remains susceptible to residual confounding and should be interpreted cautiously. While these findings are encouraging, we recognise that heterogeneity in treatment duration/doses, types of statins used, disease severity/stage and cirrhosis aetiology remain other major limitations of the current evidence base. Adequately powered, large-scale trials with standardised concomitant NSBB therapy, careful phenotyping of portal hypertension stage and sufficient follow-up will be essential to more definitively delineate the independent (and potentially synergistic) effects of statin therapy on clinically meaningful endpoints. In the interim, we continue to support the Baveno VII [9] recommendation to encourage statin use in patients with cirrhosis who have an approved indication, with appropriate caution in decompensated disease. At the same time, we note with excitement that the growing body of evidence raises the possibility that statins may ultimately assume a broader role as disease-modifying agents in cirrhosis. Bernardo de Faria Moraes: conceptualization, writing – original draft, methodology, formal analysis, data curation. Gustavo André Pedral Diniz Leite: conceptualization, investigation. Igor Boechat Silveira: conceptualization, investigation. Gabriel André Pedral Diniz Leite: conceptualization, investigation. Maria Luisa Motta Fonseca: conceptualization, investigation. Leonardo Corrêa Suffert: conceptualization, investigation. Luisa Medeiros Visentini: conceptualization, investigation. Luis Pedro Possapp Beis: conceptualization, investigation. Guilherme Grossi Lopes Cançado: conceptualization, validation, supervision, writing – review and editing, data curation. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. This article is linked to Moraes et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70526 and https://doi.org/10.1111/apt.70558. The data that support the findings of this study are available from the corresponding author upon reasonable request.